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In vitro evaluation of two polyhedral boron anion derivatives as linkers for attachment of radioiodine to the anti-HER2 monoclonal antibody trastuzumab
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
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2007 (English)In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 22, no 5, 585-596 p.Article in journal (Refereed) Published
Abstract [en]

Improving intracellular retention is important for the use of radiohalogens in radionuclide therapy usinginternalizing antibodies. Two putative linkers for residualization of radioiodine labels, 7-(4-isothiocyanato-phenyl)undecahydro-7,8-dicarba-nido-undecaborate(1Ϫ) ion (NBI) and (4-isothiocyanato-benzylammo-nio)undecahydro-closo-dodecaborate(1Ϫ) (DABI), were analyzed. The anti-HER-2 antibody, trastuzumab,was labeled with iodine-125 using NBI and DABI linkers, and, for comparison, with the para-[125I]iodoben-zoate (PIB), and Chloramine-T (CAT) methods. The different labels were tested for residualizing prop-erties using the HER-2 overexpressing SKBR-3 cells. The cellular radioactivity retention showed thatDABI provided a 55% better retention than CAT and was 42% better than PIB after 20 hours. NBI didnot improve retention. Accumulation tests up to 21 hours showed that the HER-2-specific accumulationof radioactivity delivered with DABI was, on average, 33% higher than with the use of PIB. These DABI-dependent improvements could, with high probability, be attributed to the good residualizing propertiesof DABI. The affinity of DABI-labeled trastuzumab to SKBR-3 cells was not better than the affinity of thePIB labeled (3.2 Ϯ 1.9 nM and 0.77 Ϯ 0.39 nM, respectively). In conclusion, the use of the DABI linkerimproved intracellular retention in vitro in comparison with the other labeling methods.

Place, publisher, year, edition, pages
2007. Vol. 22, no 5, 585-596 p.
Keyword [en]
antibody, radiolabeling, polyhedral boron anion, HER-2
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94330DOI: 10.1089/cbr.2006.338ISI: 000250821800002PubMedID: 17979561OAI: oai:DiVA.org:uu-94330DiVA: diva2:168145
Available from: 2006-04-20 Created: 2006-04-20 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Antibody Mediated Radionuclide Targeting of HER-2 for Cancer Diagnostics and Therapy: Preclinical Studies
Open this publication in new window or tab >>Antibody Mediated Radionuclide Targeting of HER-2 for Cancer Diagnostics and Therapy: Preclinical Studies
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Antikroppsmedierad målsökning av radionuklider till HER-2 för cancerdiagnostik och terapi : Prekliniska studier
Abstract [en]

Targeted radionuclide therapy (TRT) holds great promise for the treatment of cancer. In TRT, radioactive nuclides are delivered specifically to tumours by molecules that recognise and bind to structures overexpressed by, or specific to, cancer cells. Human epidermal growth factor receptor like protein 2 (HER-2) is an oncogene product overexpressed in e.g. urological, breast, or ovarian cancers that have been correlated to poor prognosis and resistance to hormonal therapy. There is also evidence that tumour cells retain their HER-2 overexpression in metastases.

Trastuzumab and pertuzumab are two humanised monoclonal antibodies targeting different parts of HER-2. This thesis describes the radiolabelling of these antibodies for use in TRT and diagnostics. The thesis also investigates possible methods for modifying uptake and retention of radioactivity delivered with antibodies binding to HER-2. Modification of the cellular retention of 125I by using polyhedral boron anion based linker molecules (DABI and NBI) is investigated, and it is shown that linking 125I to trastuzumab using DABI increases cellular accumulation of radioactivity by 33%. It is also shown that trastuzumab can be efficiently coupled to the positron emitter 76Br by using NBI. Furthermore, it is shown that cellular uptake of 125I can be modified by stimulating EGFR (HER-1) with EGF.

When labelled with the alpha emitter 211At, trastuzumab could specifically kill cells in vitro. This cell killing effect could be prevented by saturating the receptors of the target cells with non-radiolabelled trastuzumab.

Pertuzumab was radiolabelled with the low energy beta emitter 177Lu without losing affinity or immunocompetence. [177Lu]pertuzumab was specific to HER-2 in vitro and in vivo. This targeting conjugate was shown to increase median time to tumour progression in mice bearing xenografts of the radioresistant SKOV-3 cell line.

In conclusion, antibodies against HER-2, especially pertuzumab radiolabelled with 177Lu, show promise as TRT agents.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 140
Keyword
Molecular medicine, Neoplasm Antibodies, Targeted Radiotherapy, Radionuclide Imaging, Molekylärmedicin
Identifiers
urn:nbn:se:uu:diva-6798 (URN)91-554-6535-8 (ISBN)
Public defence
2006-05-13, Rudbeck hall, Rudbeck laboratory, Dag Hammarskölds väg 20, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-04-20 Created: 2006-04-20 Last updated: 2011-02-17Bibliographically approved

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Persson, MikaelGedda, LarsMalmström, Per-UnoTolmachev, Vladimir

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